This proposal, "Structure and function of the IRS-signaling system," is a competitive renewal of DK43808, which focuses on the IRS-signaling system discovered in the PI's laboratory. IRS-1 is the prototype docking protein that is activated by tyrosine phosphorylation. It interacts with various plasma membrane tyrosine kinases, such as the insulin and IGF receptors, to initiate signals involved in cellular growth, survival and metabolism. Recent work with mice lacking IRS-1 and IRS-2 reveals the central role of IRS-proteins in coordinating cellular growth. Mice lacking IRS-1 survive with minimal metabolic defects, but grow to 50 percent of normal size. Mice lacking IRS-2 are nearly normal size, but display selected organ hypoplasia, including small brains and pituitary glands, reduced pancreatic cell mass, and underdeveloped mammary tissue. Furthermore, IRS-proteins may promote the expansion of transformed cells in mammals which might contribute to excessive tumor burden. Thus an understanding of the role of IRS-1 and IRS-2 in cellular survival and transformation may lead to rational strategies to reduce the growth of transformed cells. The experiments proposed integrate cell culture model systems with in vivo mouse experiments to test the hypothesis that IRS-1 and IRS-2 play an important role in the growth survival and transformation of cells. This work might highlight IRS-proteins as ideal targets for inhibition of tumor growth.